In Utero Exposure to Air Pollutants and Mitochondrial Heteroplasmy in Neonates.

Mitochondria are sensitive to oxidative stress, which can be caused by traffic-related air pollution. Placental mitochondrial DNA (mtDNA) mutations have been previously linked with air pollution. However, the relationship between prenatal air pollution and cord-blood mtDNA mutations has been poorly understood. Therefore, we hypothesized that prenatal particulate matter (PM2.5) and NO2 exposures are associated with cord-blood mtDNA heteroplasmy. As part of the ENVIRONAGE cohort, 200 mother-newborn pairs were recruited. Cord-blood mitochondrial single-nucleotide polymorphisms were identified by whole mitochondrial genome sequencing, and heteroplasmy levels were evaluated based on the variant allele frequency (VAF). Outdoor PM2.5 and NO2 concentrations were determined by a high-resolution spatial-temporal interpolation method based on the maternal residential address. Distributed lag linear models were used to determine sensitive time windows for the association between NO2 exposure and cord-blood mtDNA heteroplasmy. A 5 µg/m3 increment in NO2 was linked with MT-D-Loop16311T>C heteroplasmy from gestational weeks 17-25. MT-CYTB14766C>T was negatively associated with NO2 exposure in mid pregnancy, from weeks 14-17, and positively associated in late pregnancy, from weeks 31-36. No significant associations were observed with prenatal PM2.5 exposure. This is the first study to show that prenatal NO2 exposure is associated with cord-blood mitochondrial mutations and suggests two critical windows of exposure in mid-to-late pregnancy.

The association between ambient particulate matter exposure and the telomere-mitochondrial axis of aging in newborns.

BACKGROUND: Particulate matter (PM) is associated with aging markers at birth, including telomeres and mitochondria. It is unclear whether markers of the core-axis of aging, i.e. tumor suppressor p53 (p53) and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), are associated with prenatal air pollution and whether there are underlying mechanisms. METHODS: 556 mother-newborn pairs from the ENVIRONAGE birth cohort were recruited at the East Limburg Hospital in Genk (Belgium). In placenta and cord blood, telomere length (TL) and mitochondrial DNA content (mtDNAc) were measured using quantitative real-time polymerase chain reaction (qPCR). In cord plasma, p53 and PGC-1α protein levels were measured using ELISA. Daily ambient PM2.5 concentrations during gestation were calculated using a spatial temporal interpolation model. Distributed lag models (DLMs) were applied to assess the association between prenatal PM2.5 exposure and each molecular marker. Mediation analysis was performed to test for underlying mechanisms. RESULTS: A 5 µg/m3 increment in PM2.5 exposure was associated with -11.23 % (95 % CI: -17.36 % to -4.65 %, p = 0.0012) and -7.34 % (95 % CI: -11.56 % to -2.92 %, p = 0.0014) lower placental TL during the entire pregnancy and second trimester respectively, and with -12.96 % (95 % CI: -18.84 % to -6.64 %, p < 0.001) lower placental mtDNAc during the third trimester. Furthermore, PM2.5 exposure was associated with a 12.42 % (95 % CI: -1.07 % to 27.74 %, p = 0.059) higher cord plasma p53 protein level and a -3.69 % (95 % CI: -6.97 % to -0.31 %, p = 0.033) lower cord plasma PGC-1α protein level during the third trimester. Placental TL mediated 65 % of the negative and 17 % of the positive association between PM2.5 and placental mtDNAc and cord plasma p53 protein levels, respectively. CONCLUSION: Ambient PM2.5 exposure during pregnancy is associated with markers of the core-axis of aging, with TL as a mediating factor. This study strengthens the hypothesis of the air pollution induced core-axis of aging, and may unravel a possible underlying mediating mechanism in an early-life epidemiological context.

In utero particulate matter exposure in association with newborn mitochondrial ND4L10550A>G heteroplasmy and its role in overweight during early childhood.

BACKGROUND: Mitochondria play an important role in the energy metabolism and are susceptible to environmental pollution. Prenatal air pollution exposure has been linked with childhood obesity. Placental mtDNA mutations have been associated with prenatal particulate matter exposure and MT-ND4L10550A>G heteroplasmy has been associated with BMI in adults. Therefore, we hypothesized that in utero PM2.5 exposure is associated with cord blood MT-ND4L10550A>G heteroplasmy and early life growth. In addition, the role of cord blood MT-ND4L10550A>G heteroplasmy in overweight during early childhood is investigated. METHODS: This study included 386 mother-newborn pairs. Outdoor PM2.5 concentrations were determined at the maternal residential address. Cord blood MT-ND4L10550A>G heteroplasmy was determined using Droplet Digital PCR. Associations were explored using logistic regression models and distributed lag linear models. Mediation analysis was performed to quantify the effects of prenatal PM2.5 exposure on childhood overweight mediated by cord blood MT-ND4L10550A>G heteroplasmy. RESULTS: Prenatal PM2.5 exposure was positively associated with childhood overweight during the whole pregnancy (OR = 2.33; 95% CI: 1.20 to 4.51; p = 0.01), which was mainly driven by the second trimester. In addition, prenatal PM2.5 exposure was associated with cord blood MT-ND4L10550A>G heteroplasmy from gestational week 9 - 13. The largest effect was observed in week 10, where a 5 µg/m3 increment in PM2.5 was linked with cord blood MT-ND4L10550A>G heteroplasmy (OR = 0.93; 95% CI: 0.87 to 0.99). Cord blood MT-ND4L10550A>G heteroplasmy was also linked with childhood overweight (OR = 3.04; 95% CI: 1.15 to 7.50; p = 0.02). The effect of prenatal PM2.5 exposure on childhood overweight was mainly direct (total effect OR = 1.18; 95% CI: 0.99 to 1.36; natural direct effect OR = 1.20; 95% CI: 1.01 to 1.36)) and was not mediated by cord blood MT-ND4L10550A>G heteroplasmy. CONCLUSIONS: Cord blood MT-ND4L10550A>G heteroplasmy was linked with childhood overweight. In addition, in utero exposure to PM2.5 during the first trimester of pregnancy was associated with cord blood MT-ND4L10550A>G heteroplasmy in newborns. Our analysis did not reveal any mediation of cord blood MT-ND4L10550A>G heteroplasmy in the association between PM2.5 exposure and childhood overweight.

The telomere-mitochondrial axis of aging in newborns.

Aging starts at the beginning of life as evidenced by high variability in telomere length (TL) and mitochondrial DNA content (mtDNAc) at birth. Whether p53 and PGC-1α are connected to these age-related markers in early life is unclear. In this study, we hypothesized that these hallmarks of aging are associated at birth. In 613 newborns from the ENVIRONAGE birth cohort, p53 and PGC-1α protein levels were measured in cord plasma, while TL and mtDNAc were measured in both cord blood and placental tissue. Cord blood methylation data of genes corresponding to the measured protein levels were available from the Human MethylationEPIC 850K BeadChip array. Pearson correlations and linear regression models were applied while accounting for selected covariates. In cord, a 10% increase in TL was associated with 5.22% (95% CI: 3.26 to 7.22; p < 0.0001) higher mtDNAc and -2.66% (95% CI: -5.04 to -0.23%; p = 0.032) lower p53 plasma level. In placenta, a 10% increase in TL was associated with 5.46% (95% CI: 3.82 to 7.13%; p < 0.0001) higher mtDNAc and -2.42% (95% CI: -4.29 to -0.52; p = 0.0098) lower p53 plasma level. Methylation level of TP53 was correlated with TL and mtDNAc in cord blood and with cord plasma p53 level. Our study suggests that p53 may be an important factor both at the protein and methylation level for the telomere-mitochondrial axis of aging at birth.

Glyphosate and AMPA exposure in relation to markers of biological aging in an adult population-based study.

BACKGROUND/AIM: Glyphosate, a broad-spectrum herbicide, and its main metabolite aminomethylphosphonic acid (AMPA) are persistent in the environment. Studies showed associations between glyphosate or AMPA exposure and several adverse cellular processes, including metabolic alterations and oxidative stress. OBJECTIVE: To determine the association between glyphosate and AMPA exposure and biomarkers of biological aging. METHODS: We examined glyphosate and AMPA exposure, mtDNA content and leukocyte telomere length in 181 adults, included in the third cycle of the Flemish Environment and Health Study (FLEHSIII). DNA was isolated from leukocytes and the relative mtDNA content and telomere length were determined using qPCR. Urinary glyphosate and AMPA concentrations were measured by Gas Chromatography-Tandem Mass Spectrometry (GC-MS-MS). We used multiple linear regression models to associate mtDNA content and leukocyte telomere length with glyphosate or AMPA exposure while adjusting for confounding variables. RESULTS: A doubling in urinary AMPA concentration was associated with 5.19% (95% CI: 0.49 to 10.11; p = 0.03) longer leukocyte telomere length, while no association was observed with urinary glyphosate concentration. No association between mtDNA content and urinary glyphosate nor AMPA levels was observed. CONCLUSIONS: This study showed that AMPA exposure may be associated with telomere biology in adults.

Dynamics of skin microvascular blood flow in 4-6-year-old children in association with pre- and postnatal black carbon and particulate air pollution exposure.

BACKGROUND: A growing body of evidence indicates that cardiovascular health in adulthood, particularly that of the microcirculation, could find its roots during prenatal development. In this study, we investigated the association between pre- and postnatal air pollution exposure on heat-induced skin hyperemia as a dynamic marker of the microvasculature. METHODS: In 139 children between the ages of 4 and 6 who are followed longitudinally within the ENVIRONAGE birth cohort, we measured skin perfusion by Laser Doppler probes using the Periflux6000. Residential black carbon (BC), particulate (PM10 and PM2.5) air pollution, and nitrogen dioxide (NO2) levels were modelled for each participant's home address using a high-resolution spatiotemporal model for multiple time windows. We assessed the association between skin hyperemia and pre- and postnatal air pollution using multiple regression models while adjusting for relevant covariates. RESULTS: Residential BC exposure during the whole pregnancy averaged (IQR) 1.42 (1.22-1.58) µg/m3, PM10 18.88 (16.64 - 21.13) µg/m3, PM2.5 13.67 (11.5 - 15.56) µg/m3 and NO2 18.39 (15.52 - 20.31) µg/m3. An IQR increment in BC exposure during the third trimester of pregnancy was associated with an 11.5 % (95% CI: -20.1 to -1.9; p = 0.020) lower skin hyperemia. Similar effect estimates were retrieved for PM10, PM2.5 and NO2 (respectively 13.9 % [95% CI: -21.9 to -3.0; p = 0.003], 17.0 % [95% CI: -26.7 to -6.1; p = 0.004] and 12.7% [95 % CI: -22.2 to -1.9; p = 0.023] lower skin hyperemia). In multipollutant models, PM2.5 showed the strongest inverse association with skin hyperemia. Postnatal exposure to BC, PM10, PM2.5 or NO2, was not associated with skin hyperemia at the age of 4 to 6, and did not alter the previous reported prenatal associations when taken into account. CONCLUSION: Our findings support that BC, particulate air pollution, and NO2 exposure, even at low concentrations, during prenatal life, can have long-lasting consequences for the microvasculature. This proposes a role of prenatal air pollution exposures over and beyond postnatal exposure in the microvascular alterations which were persistent into childhood.

Glomerular function in relation to fine airborne particulate matter in a representative population sample.

From 1990 until 2017, global air-pollution related mortality increased by 40%. Few studies addressed the renal responses to ultrafine particulate [≤ 2.5 µm (PM2.5)], including black carbon (BC), which penetrate into the blood stream. In a Flemish population study, glomerular filtration estimated from serum creatinine (eGFR) and the urinary albumin-to-creatinine ratio were measured in 2005-2009 in 820 participants (women, 50.7%; age, 51.1 years) with follow-up of 523 after 4.7 years (median). Serum creatinine, eGFR, chronic kidney disease (eGFR < 60 mL/min/1.73 m2) and microalbuminuria (> 3.5/> 2.5 mg per mmol creatinine in women/men) were correlated in individual participants via their residential address with PM2.5 [median 13.1 (range 0.3-2.9) µg/m3] and BC [1.1 (0.3-18) µg/m3], using mixed models accounting for address clusters. Cross-sectional and longitudinally, no renal outcome was associated with PM2.5 or BC in models adjusted for sex and baseline or time varying covariables, including age, blood pressure, heart rate, body mass index, plasma glucose, the total-to-HDL serum cholesterol ratio, alcohol intake, smoking, physical activity, socioeconomic class, and antihypertensive treatment. The subject-level geocorrelations of eGFR change with to BC and PM2.5 were 0.13 and 0.02, respectively (P ≥ 0.68). In conclusion, in a population with moderate exposure, renal function was unrelated to ultrafine particulate.

Child buccal telomere length and mitochondrial DNA content as biomolecular markers of ageing in association with air pollution.

BACKGROUND: Pro-inflammatory conditions such as air pollution might induce biological ageing. However, the available evidence on such an impact in children is still very scarce. We studied in primary schoolchildren the association of ambient residential air pollution exposure with telomere length (TL) and mitochondrial DNA content (mtDNAc), two important targets of the core axis of ageing. METHODS: Between 2012 and 2014, buccal TL and mtDNAc were repeatedly assessed using qPCR in 197 Belgian primary schoolchildren (mean age 10.3 years) as part of the COGNAC study. At the child's residence, recent (week), sub-chronic (month) and chronic (year) exposure to nitrogen dioxide (NO2), particulate matter ≤ 2.5 µm (PM2.5) and black carbon (BC) were estimated using a high resolution spatiotemporal model. A mixed-effects model with school and subject as random effect was used while adjusting for a priori chosen covariates. RESULTS: An interquartile range (IQR) increment (1.9 µg/m3) in chronic PM2.5 exposure was associated with a 8.9% (95% CI: -15.4 to -1.9%) shorter TL. In contrast to PM2.5, chronic exposure to BC and NO2 was not associated with TL but recent exposure to BC and NO2 showed significant inverse associations with TL: an IQR increment in recent exposure to BC (0.9 µg/m3) and NO2 (10.2 µg/m3) was associated with a 6.2% (95% CI: -10.6 to -1.6%) and 6.4% (95% CI: -11.8 to -0.7%) shorter TL, respectively. Finally, an IQR increment in chronic PM2.5 exposure was associated with a 12.7% (95% CI: -21.7 to -2.6%) lower mtDNAc. However, no significant associations were seen for NO2 and BC or for other exposure windows. CONCLUSION: Chronic exposure to PM2.5 below the EU threshold was associated with child's shorter buccal TL and lower mtDNAc, while traffic-related pollutants (BC and NO2) showed recent effects on telomere biology. Our data add to the literature on air pollution-induced effects of TL and mtDNAc, two measures part of the core axis of cellular ageing, from early life onwards.

Ambient air pollution exposure during the late gestational period is linked with lower placental iodine load in a Belgian birth cohort.

BACKGROUND: Adequate intake of iodine is required for the production of thyroid hormones and contributes in pregnant women to a healthy brain development and growth in their offspring. To date, some evidence exists that fine particulate air pollution is linked with the fetal thyroid hormone homeostasis. However, possible effects of air pollutants on the placental iodine storage have not been investigated so far. OBJECTIVES: We investigated the association between air pollution exposure to particulate matter with a diameter less than 2.5 µm (PM2.5), NO2, and black carbon and the placental iodine load. METHODS: The current study is part of the ENVIRONAGE birth cohort and included 470 mother-newborn pairs. Iodine concentrations were measured in placental tissue. A high-resolution air pollution model was used to estimate the daily exposure to PM2.5, NO2, and black carbon over the entire pregnancy based on the maternal residential addresses. Distributed lag nonlinear models (DLNMs) were used to estimate gestational week-specific associations between placental iodine concentrations and the air pollutants to understand the impact of specific exposure windows. RESULTS: PM2.5 showed a positive association with placental iodine concentration between the 16th and 22nd week of gestation. In contrast, a significant inverse association between PM2.5 and placental iodine concentration was observed in gestational weeks 29-35. The effect estimate, for a 5 µg/m3 increment in PM2.5 concentration, was the strongest at week 32 (ß -0.11 µg/kg; 95%CI: -0.18 to -0.03). No associations were observed between placental iodine concentrations and NO2 or black carbon. Assuming causality, we estimated that placental iodine mediated 26% (-0.33 pmol/L; 95%CI: -0.70 to 0.04 pmol/L) of the estimated effect of a 5 µg/m3 increment in PM2.5 exposure on cord blood free thyroxine (FT4) concentrations. CONCLUSION: In utero exposure to particulate matter during the third trimester of pregnancy is linked with a lower placental iodine load. Furthermore, the effect of air pollution on cord blood FT4 levels was partially mediated by the placental iodine load.

Mitochondrial DNA methylation in placental tissue: a proof of concept study by means of prenatal environmental stressors.

While previous studies have demonstrated that prenatal exposure to environmental stressors is associated with mitochondrial DNA (mtDNA) methylation, more recent investigations are questioning the accuracy of the methylation assessment and its biological relevance. In this study, we investigated placental mtDNA methylation while accounting for methodological issues such as nuclear contamination, bisulphite conversion, and PCR bias. From the ENVIRONAGE birth cohort, we selected three groups of participants (n = 20/group). One group with mothers who smoked during pregnancy (average 13.2 cig/day), one group with high air pollutant exposure (PM2.5: 16.0 ± 1.4 µg/m3, black carbon: 1.8 ± 0.3 µg/m3) and one control group (non-smokers, PM2.5: 10.6 ± 1.7 µg/m3, black carbon: 0.9 ± 0.1 µg/m3) with low air pollutant exposure. DNA methylation levels were quantified in two regions of the displacement loop control region (D-loop and LDLR2) by bisulphite pyrosequencing. Additionally, we measured DNA methylation on nuclear genes involved in mitochondrial maintenance (PINK1, DNA2, and POLG1) and assessed mtDNA content using qPCR. Absolute D-loop methylation levels were higher for mothers that smoked extensively (+0.36%, 95% CI: 0.06% to 0.66%), and for mothers that were highly exposed to air pollutants (+0.47%, 95% CI: 0.20% to 0.73%). The relevance of our findings is further supported, as D-loop methylation levels were correlated with placental mtDNA content (r = -0.40, p = 0.002) and associated with birth weight (-106.98 g, 95% CI: -209.60 g to -4.36 g for an IQR increase in D-loop methylation). Most notably, our data demonstrates relevant levels of mtDNA methylation in placenta tissue, with significant associations between prenatal exposure to environmental stressors and D-loop methylation.

Association of Retinal Microvascular Characteristics With Short-term Memory Performance in Children Aged 4 to 5 Years.

Importance: Neurocognitive functions develop rapidly in early childhood and depend on the intrinsic cooperation between cerebral structures and the circulatory system. The retinal microvasculature can be regarded as a mirror image of the cerebrovascular circulation. Objective: To investigate the association between retinal vessel characteristics and neurological functioning in children aged 4 to 5 years. Design, Setting, and Participants: In this cohort study, mother-child pairs were recruited at birth from February 10, 2010, to June 24, 2014, and renewed consent at their follow-up visit from December 10, 2014, to July 13, 2018. Participants were followed up longitudinally within the prospective Environmental Influence on Aging in Early Life birth cohort. A total of 251 children underwent assessment for this study. Data were analyzed from July 17 to October 30, 2019. Main Outcomes and Measures: Retinal vascular diameters, the central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE), vessel tortuosity, and fractal dimensions were determined. Attention and psychomotor speed, visuospatial working memory, and short-term visual recognition memory were assessed by the Cambridge Neuropsychological Test Automated Battery, including the following tasks: Motor Screening (MOT), Big/Little Circle (BLC), Spatial Span (SSP), and Delayed Matching to Sample (DMS). Results: Among the 251 children included in the assessment (135 girls [53.8%]; mean [SD] age, 4.5 [0.4] years), for every 1-SD widening in CRVE, the children performed relatively 2.74% (95% CI, -0.12 to 5.49; P = .06) slower on the MOT test, had 1.76% (95% CI, -3.53% to -0.04%; P = .04) fewer correct DMS assessments in total, and made 2.94% (95% CI, 0.39 to 5.29; P = .02) more errors given a previous correct answer in the DMS task on multiple linear regression modeling. For every 1-SD widening in CRAE, the total percentage of errors and errors given previous correct answers in the DMS task increased 1.44% (95% CI, -3.25% to 0.29%; P = .09) and 2.30% (95% CI, -0.14% to 4.61%; P = .07), respectively. A 1-SD higher vessel tortuosity showed a 4.32% relative increase in latency in DMS task performance (95% CI, -0.48% to 9.12%; P = .07). Retinal vessel characteristics were not associated with BLC and SSP test outcomes. Conclusions and Relevance: These findings suggest that children's microvascular phenotypes are associated with short-term memory and that changes in the retinal microvasculature may reflect neurological development during early childhood.

Association of Parental Socioeconomic Status and Newborn Telomere Length.

Importance: Low socioeconomic status is associated with higher all-cause mortality and risks for aging-related diseases. Biological aging is a potential process underlying health conditions related to social disadvantages, which may be present from birth onward. Objective: To evaluate the association of parental socioeconomic status with telomere length (TL) at birth, a marker of biological aging. Design, Setting, and Participants: This prospective birth cohort study was conducted among 1504 mother-newborn pairs in Belgium recruited between February 1, 2010, and July 1, 2017. Exposures: Parental socioeconomic measures, including maternal educational level, occupation, paternal educational level, and neighborhood income based on median annual household income. Main Outcomes and Measures: Mean relative TL was measured in cord blood and placental tissue. By constructing a principal component, an integrative socioeconomic measure was derived that integrates parental socioeconomic status and neighborhood income. Multivariable adjusted regression analyses were performed to associate the integrative socioeconomic measure and TL at birth. Results: In 1026 newborns (517 boys; mean [SD] gestational age, 39.2 [1.4] weeks), a higher socioeconomic status was associated with longer cord blood TL and placental TL. Each unit increment in the integrative socioeconomic status measure was associated with 2.1% (95% CI, 0.9%-3.4%; P < .001) longer cord blood TL in boys, while no association was observed for girls (0.5% longer cord blood TL; 95% CI, -0.9% to 1.8%; P = .50). The sex-specific socioeconomic status interaction revealed a stronger association in boys compared with newborn girls (1.6%; 95% CI, 0.02%-3.3%; P = .047 for interaction). In placental tissue, higher socioeconomic status was associated with 1.8% (95% CI, 0.3%-3.3%; P = .02) longer TL in newborn boys but not in girls (0.4% longer TL; 95% CI, -1.2% to 2.0%; P = .63). For placental tissue, no sex and socioeconomic status interaction on TL was observed (1.4%; 95% CI, -0.5% to 3.4%; P = .16 for interaction). Conclusions and Relevance: This study suggests that parental socioeconomic status is associated with newborn TL, especially in boys. The results indicate that familial social economic factors are associated with the potential cellular longevity of the next generation, with a potential higher transgenerational vulnerability for newborn boys.

Association of Prenatal Exposure to Ambient Air Pollution With Circulating Histone Levels in Maternal Cord Blood.

Importance: Exposure to ambient air pollution has been associated with the risk of carcinogenesis in later life. Changes in histone modifications might have long-term adverse health effects. Objective: To investigate the association of prenatal exposure to ambient air pollution with levels of circulating total histone H3 and specific trimethylation marks (ie, H3 lysine 4, H3 lysine 36) in maternal cord blood. Design, Setting, and Participants: The Environmental Influence on Aging (ENVIRONAGE) birth cohort study included 609 mothers and their newborns. Participants were recruited when mothers entered the Hospital East Limburg (Genk, Belgium) for delivery between February 2010 and January 2017. The inclusion criteria were singleton pregnancies and the ability to fill out questionnaires in Dutch. Data analysis was conducted from March to August 2019. Exposures: Exposure to particulate matter with a diameter less than 2.5 µm (PM2.5), black carbon, and nitrogen dioxide during pregnancy was modeled with a high-resolution air pollution model on the basis of maternal address for each trimester of pregnancy as well as for the entire pregnancy. Main Outcomes and Measures: Circulating total histone H3 levels and specific trimethylation marks (ie, trimethylated H3 lysine 4 and trimethylated H3 lysine 36) in cord blood. Results: A total of 609 mother-newborn pairs were included in the study. Mean (SD) maternal age was 29.3 (4.6) years, 391 mothers (64.2%) never smoked, and 314 (51.3%) had a high education level. Overall, 322 newborns (52.4%) were boys, and mean (SD) birth weight was 3414 (485) g. Participants experienced mean (SD) exposure to PM2.5, black carbon, and nitrogen dioxide of 13.4 (2.6) µg/m3, 1.29 (0.31) µg/m3, and 17.98 (4.57) µg/m3, respectively, during their entire pregnancies. Trimethylated H3 lysine 4 and total histone H3 were positively associated with gestational PM2.5 exposure, with a 74.4% increment (95% CI, 26.7% to 140.2%, P < .001) and a 40.2% increment (95% CI, 24.1% to 58.3%, P < .001), respectively, observed for each 5-µg/m3 increase in PM2.5 exposure during the entire pregnancy. For the same exposure window, trimethylated H3 lysine 36 levels were inversely associated with PM2.5 exposure (-34.4%; 95% CI, -50.1% to -13.7%; P = .003). Exposure to black carbon during the entire pregnancy was positively associated with trimethylated H3 lysine 4 (38.4%; 95% CI, 6.2% to 80.3%; P = .003). Conclusions and Relevance: Associations of ambient air pollution with cord plasma histone H3 modifications during early life might indicate that circulating histones are a risk factor in the development of air pollution-associated disease later in life. Additional study is required to correctly estimate the long-term consequences of our findings.

Children's microvascular traits and ambient air pollution exposure during pregnancy and early childhood: prospective evidence to elucidate the developmental origin of particle-induced disease.

BACKGROUND: Particulate matter exposure during in utero life may entail adverse health outcomes later in life. The microvasculature undergoes extensive, organ-specific prenatal maturation. A growing body of evidence shows that cardiovascular disease in adulthood is rooted in a dysfunctional fetal and perinatal development, in particular that of the microcirculation. We investigate whether prenatal or postnatal exposure to PM2.5 (particulate matter with a diameter ≤ 2.5 µm) or NO2 is related to microvascular traits in children between the age of four and six. METHODS: We measured the retinal microvascular diameters, the central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE), and the vessel curvature by means of the tortuosity index (TI) in young children (mean [SD] age 4.6 [0.4] years), followed longitudinally within the ENVIRONAGE birth cohort. We modeled daily prenatal and postnatal PM2.5 and NO2 exposure levels for each participant's home address using a high-resolution spatiotemporal model. RESULTS: An interquartile range (IQR) increase in PM2.5 exposure during the entire pregnancy was associated with a 3.85-µm (95% CI, 0.10 to 7.60; p = 0.04) widening of the CRVE and a 2.87-µm (95% CI, 0.12 to 5.62; p = 0.04) widening of the CRAE. For prenatal NO2 exposure, an IQR increase was found to widen the CRVE with 4.03 µm (95% CI, 0.44 to 7.63; p = 0.03) and the CRAE with 2.92 µm (95% CI, 0.29 to 5.56; p = 0.03). Furthermore, a higher TI score was associated with higher prenatal NO2 exposure. We observed a postnatal effect of short-term PM2.5 exposure on the CRAE and a childhood NO2 exposure effect on both the CRVE and CRAE. CONCLUSIONS: Our results link prenatal and postnatal air pollution exposure with changes in a child's microvascular traits as a fundamental novel mechanism to explain the developmental origin of cardiovascular disease.

Pre-admission air pollution exposure prolongs the duration of ventilation in intensive care patients.

PURPOSE: Air pollutant exposure constitutes a serious risk factor for the emergence or aggravation of (existing) pulmonary disease. The impact of pre-intensive care ambient air pollutant exposure on the duration of artificial ventilation was, however, not yet established. METHODS: The medical records of 2003 patients, admitted to the intensive care unit (ICU) of the Antwerp University Hospital (Flanders, Belgium), who were artificially ventilated on ICU admission or within 48 h after admission, for the duration of at least 48 h, were analyzed. For each patient's home address, daily air pollutant exposure [particulate matter with an aerodynamic diameter ≤ 2.5 µm (PM2.5) and ≤ 10 µm (PM10), nitrogen dioxide (NO2) and black carbon (BC)] up to 10 days prior to hospital admission was modeled using a high-resolution spatial-temporal model. The association between duration of artificial ventilation and air pollution exposure during the last 10 days before ICU admission was assessed using distributed lag models with a negative binomial regression fit. RESULTS: Controlling for pre-specified confounders, an IQR increment in BC (1.2 µg/m3) up to 10 days before admission was associated with an estimated cumulative increase of 12.4% in ventilation duration (95% CI 4.7-20.7). Significant associations were also observed for PM2.5, PM10 and NO2, with cumulative estimates ranging from 7.8 to 8.0%. CONCLUSION: Short-term ambient air pollution exposure prior to ICU admission represents an unrecognized environmental risk factor for the duration of artificial ventilation in the ICU.

Breastfeeding predicts blood mitochondrial DNA content in adolescents.

Nutrition during early childhood is linked to metabolic programming. We hypothesized that breastfeeding has long-term consequences on the energy metabolism exemplified by mitochondrial DNA (mtDNA). As part of the third cycle of the Flemish Environment and Health Study (FLEHSIII) cohort, 303 adolescents aged 14-15 years were included. We associated breastfeeding and blood mtDNA content 14-15 years later while adjusting for confounding variables. Compared with non-breastfed adolescents, mtDNA content was 23.1% (95%CI: 4.4-45.2; p = 0.013) higher in breastfed adolescents. Being breastfed for 1-10 weeks, 11-20 weeks, and >20 weeks, was associated with a higher mtDNA content of respectively 16.0% (95%CI: -7.1-44.9; p = 0.191), 23.5% (95%CI: 0.8-51.3; p = 0.042), and 31.5% (95%CI: 4.3-65.7; p = 0.021). Our study showed a positive association between breastfeeding and mtDNA content in adolescents which gradually increased with longer periods of breastfeeding. Higher mtDNA content may be an underlying mechanism of the beneficial effects of breastfeeding on children's metabolism.

Variability of iodine concentrations in the human placenta.

Iodine is an essential trace element, necessary for the production of thyroid hormones, which play a key role in optimal foetal growth and (neuro-) development. To date, iodine deficiency remains a health burden in many countries. We investigated the variability of placental iodine concentrations within and between individuals. We used 20 mother-neonate pairs from the ENVIRONAGE birth cohort, took samples at three standardized locations of the placentas, pooled and digested them, and determined the iodine concentrations using an ICP-MS method as an alternative for the Sandell-Kolthoff method. The variability between and within the three sample regions was calculated using the intra-class correlation coefficient (ICC) from the variance components of mixed models. With the Friedman test, the differences between placental biopsies were assessed. The ICC showed a higher between-placenta (68.6%) than within-placenta (31.4%) variability. Subsequently, we used our optimized method to determine iodine concentrations in 498 mother-neonate pairs, which averaged 26.1 µg/kg. For 96 mothers, the urinary iodine concentrations were also determined, which showed no correlation with the placental iodine storage, as was expected. Future studies are necessary to explore the effects of these placental iodine concentrations in relation to health outcomes of mother and child at birth and later in life.

Placental mitochondrial DNA content is associated with childhood intelligence.

BACKGROUND: Developmental processes in the placenta and the fetal brain are shaped by the similar biological signals. Evidence accumulates that adaptive responses of the placenta may influence central nervous system development. We hypothesize that placental mtDNA content at birth is associated with intelligence in childhood. In addition, we investigate if intra-pair differences in mtDNA content are associated with intra-pair differences in intelligence. METHODS: Relative mtDNA content was measured using qPCR in placental tissue of 375 children of the East Flanders Prospective Twin Survey. Intelligence was assessed with the Wechsler Intelligence Scale for Children-Revised (WISC-R) between 8 and 15 years old. We accounted for sex, gestational age, birth weight, birth year, zygosity and chorionicity, cord insertion, age at measurement, indicators of socioeconomic status, smoking during pregnancy, and urban environment. RESULTS: In multivariable adjusted mixed modelling analysis, each doubling in placental mtDNA content was associated with 2.0 points (95% CI 0.02 to 3.9; p = 0.05) higher total and 2.3 points (95% CI 0.2 to 4.3; p = 0.03) higher performance IQ in childhood. We observed no association between mtDNA content and verbal intelligence. Intra-pair differences in mtDNA content and IQ were significantly (p = 0.01) correlated in monozygotic-monochorionic twin pairs, showing that the twin with the highest mtDNA content was 1.9 times more likely (p = 0.05) to have the highest IQ. This was not observed in dichorionic twin pairs. CONCLUSIONS: We provide the first evidence that placental mtDNA content is associated with childhood intelligence. This emphasizes the importance of placental mitochondrial function during in utero life on fetal brain development with long-lasting consequences.

Neonatal blood pressure in association with prenatal air pollution exposure, traffic, and land use indicators: An ENVIRONAGE birth cohort study.

Elevated blood pressure (BP) in early life may lead to cardiovascular morbidity and mortality in later life. Air pollution exposure has been associated with increased BP in adults and children, but the contribution of prenatal air pollution exposure has rarely been assessed. In addition, we are not aware of any study on neonatal BP and maternal residential traffic and land use indicators during pregnancy. We investigated the association between newborn BP and prenatal air pollution, traffic and land use indicators, using data from 427 term (gestational age > 36 weeks) births from the ENVIRONAGE birth cohort. Newborn BP was measured using an automated device within 4 days after birth. Daily maternal residential air pollutants during pregnancy, including particulate matter with an aerodynamic diameter ≤ 2.5 µm (PM2.5) and ≤10 µm (PM10), black carbon (BC), and nitrogen dioxide (NO2), were modelled using a high-resolution spatial-temporal model. The association between newborn BP and air pollution during the last 15 weeks of pregnancy was assessed using distributed lag models. Each 5 µg/m3 increment in prenatal PM2.5 exposure was associated with a 2.4 mm Hg (95% CI, 0.5 to 4.2) higher systolic and a 1.8 mm Hg (95% CI, 0.2 to 3.5) higher diastolic BP at birth. Overall estimates for PM10 were similar but those for NO2 and BC did not reach significance. Associations between newborn BP and exposures during the last 4 to 5 weeks of pregnancy were significant for all pollutants. An IQR (20.3%) increment in percentage residential greenness in a 5 km radius was associated with a 1.2 mm Hg (95% CI, -2.5 to 0.1; p = 0.07) lower systolic and a 1.2 mm Hg (95% CI, -2.4 to -0.0; p = 0.05) lower diastolic BP. An IQR (4.1%) increment in percentage industrial area in a 5 km radius was associated with a 1.0 mm Hg (95% CI, 0.1 to 1.9; p = 0.03) higher diastolic BP. Residential traffic indicators did not significantly associate with newborn BP. Prenatal air pollution exposure, greenness, and industrial area at maternal residence may affect offspring BP from birth onwards.

Exposure to Environmental Pollutants and Their Association with Biomarkers of Aging: A Multipollutant Approach.

Mitochondrial DNA (mtDNA) content and telomere length are putative aging biomarkers and are sensitive to environmental stressors, including pollutants. Our objective was to identify, from a set of environmental exposures, which exposure is associated with leukocyte mtDNA content and telomere length in adults. This study includes 175 adults from 50 to 65 years old from the cross-sectional Flemish Environment and Health study, of whom leukocyte telomere length and mtDNA content were determined using qPCR. The levels of exposure of seven metals, 11 organohalogens, and four perfluorinated compounds (PFHxS, PFNA, PFOA, PFOS) were measured. We performed sparse partial least-squares regression analyses followed by ordinary least-squares regression to assess the multipollutant associations. While accounting for possible confounders and coexposures, we identified that urinary cadmium (6.52%, 95% confidence interval, 1.06, 12.28), serum hexachlorobenzene (2.89%, 018, 5.68), and perfluorooctanesulfonic acid (11.38%, 5.97, 17.08) exposure were positively associated ( p < 0.05) with mtDNA content, while urinary copper (-9.88%, -14.82, -4.66) and serum perfluorohexanesulfonic acid (-4.75%, -8.79, -0.54) exposure were inversely associated with mtDNA content. Urinary antimony (2.69%, 0.45, 4.99) and mercury (1.91%, 0.42, 3.43) exposure were positively associated with leukocyte telomere length, while urinary copper (-3.52%, -6.60, -0.34) and serum perfluorooctanesulfonic acid (-3.64%, -6.60, -0.60) showed an inverse association. Our findings support the hypothesis that environmental pollutants interact with molecular hallmarks of aging.